5,5-disubstituted hydantoins



nite States 3,452,040 5,5-DISUBSTITUTED HYDANTOINS Andre L. Langis,Montreal, Quebec, Canada, assignor to American Home ProductsCorporation, New York, N.Y., a corporation of Delaware No Drawing. FiledJan. 5, 1966, Ser. No. 531,322 Int. Cl. (107d 49/32; A61k 27/00 U.S. Cl.260-3095 6 Claims ABSTRACT OF THE DISCLOSURE There are disclosed hereinthe following S-methyl hydantoins substituted in positionwith thefollowing substituents:

and methods for their preparation and use are also disclosed.

The present invention relates to new 5,5-disubstituted hydantoins and totheir pharmacologically acceptable salts as well as to intermediatesused in their preparation. The compounds of this invention possessanti-inflammatory activities when administered locally or orally, andare useful in the treatment of inflammatory conditions. For localadministration they may be formulated in the form of solutions, creams,or lotions, containing from 0.5 to 5 percent of the active ingredient,and may be applied locally to the inflamed area several times a day. Fororal administration, they may be formulated with excipients such asstarch, lactose, magnesium stearate or magnesium silicate in the form oftablets or capsules containing from 25 to 250 mg. per dosage form.

More specifically, the compounds of this invention possess the generalstructure.

in which R represents a monovalent basic radical such as the radical ofa nitrogen-containing heterocycle, for example, piperidine, morpholine,tetrahydroisoquinoline, N- benzylpiperazine, or hexamethylenimiue, or ofa substituted benzylamine, such as, for example, N-isopropylbenzylamine,or N-methylbenzylamine; the benzyl radical in the latter group ofsubstituents may also be suitably substituted, with substituents such ashalogen or lower alkoxy groups being preferred.

The compounds of this invention may be conveniently prepared by reactinga suitably substituted secondary amine of the formula RR NH, in which Rhas the significance defined above and R represents a lower alkyl groupcontaining from one to three carbon atoms, or is a part of theheterocycle represented by the symbol R, with 3,452,040 Patented June24, 1969 chloroacetone to obtain the intermediate (tertiary amino)-ketone of the formula RR NCH COCH in which R and R have the significancedefined above. Examples of such (tertiary amino)ketones areN-morpholinylacetone, N-1,2,3,4-tetrahydroisoquinolylacetone,

N '-benzyl-N-piperazinylacetone, N-hexamethyleneiminoacetone,N-benzyl-N-methylaminoacetone, N-2-chlorobenzyl-N-methylaminoacetone,N-3 ,4-dichlorobenzyl-N-methylaminoacetone,N-4-methoxybenzyl-N-methylaminoacetone,N-3-methoxy-benzyl-N-methylaminoacetone,N-benzyl-N-isopropylaminoacetone andN-3,4-dimethoxybenzyl-N-methylaminoacetone.

The latter (tertiary aminoJketone is then reacted with ammoniumcarbonate and potassium cyanide in the conventional manner to obtain thecorresponding hydantoin. If desired, the latter compound may then bereacted with a substantially equimolar amount of a pharmacologicallyacceptable acid to obtain the corresponding pharmacologically acceptablesalts.

The following formulae and examples will illustrate this invention.

RR NH CICHzCOOHz BR NCHQCOCHa I'l /C O-NH R-N-CHT-C-CHS NH-C 0 Example 12-chloroacet0ne (74.0 g., 0.8 mole) is added dropwise over a period offour hours to a solution of 68.0 g. (0.8 mole) of piperidine and g.(0.85 mole) of sodium carbonate in 650 ml. of water. The reactionmixture is stored at room temperature for twenty hours, extracted withbenzene, the extract washed with water, dried, and the solventevaporated under reduced pressure. The residue is distilled underreduced pressure to yield N-piperidylacetone B.P. C./9 mm.

In the same manner, but using the appropriate amine instead ofpiperidine, the following substituted acetones, some of which arecharacterized as their oxalate salts, are also obtained;N-morpholinylacetone, B.P. 80 C./0.7 mm.;N-1,2,3,4-tetrahydroisoquinolylacetone, B.P. 110 C./0.5 mm.;N-benzyl-N-piperazinylacetone; N-hexamethyleneiminoacetone, B.P. 9698C./l3 mm.; N-benzyl-N-isopropylaminoacetone, B.P. 128 C./12 mm.; 'N-benzyl-N-methylaminoacetone, B.P. 108 C./8 mm.; N- 3,4dichlorobenzyl-N-methylaminoacetone, oxalate salt, M.P. 151l53 C.;N-Z-chlorobenzyl-N-methylaminoacetone, B.P. 132 C./ 8 mm.;N-3-methoxylbenzyl-N-methylaminoacetone; N3,4-dimethoxybenzyl-N-methylaminoacetone, oxalate salt, M.'P. 166168 C.;N-4-methoxybenzyl-N-methylaminoacetone, oxalate salt, M.-P. 168 170 C. 1

Example 2 N-piperidylacetone (45.39, 0.322 mole), obtained as describedin Example 1, is added to a mixture of ammoni um carbonate (309.1 g.,3.22 mole) and potassium cyanide (41.9 g., 0.644 mole). The mixture isstored at 55 C. for ten hours and then at room temperature for anadditional ten hours. The solution is evaporated to one-third of theoriginal volume and the crystals are collected by filtration.S-methyl-S-N-piperidyl-methylhydantoin is recrystallized from ethanol toM.P. 228-232" C. The compound is identified by elemental analysis.

Examples 3 to 13 are obtained and are identified by elemental analysis.

Example Starting material Final product No. (tort-amino) ketonehydantoin M.P., C-

3 N-morpholinylacetone. 5-methy1-5-N- 206-210 morpholinomethyl. 4N1,2,3,4tetrahydro- 5-methyl-5-(N-l,2,3,4- 207-210 isoquinolylacetone.tctrahydroisoqninolylmethyl. 5 N-benzyl-N-piper- 5-methyl-5-(N- 210-113azinylaeetone. benzyl-N-piperazinylmethyl). 6 N-hexamethylene-5-methyl-5-hexa- 224-226 iminoacetone. methyleneiminomethyl. 7N-benzyl-N-methyl- S-methyl-fi-N-methyl- 196-200 aminoacetone.benzylaminomethyl. 8 N-2-chlorobenzyl-N- 5-rnethyl-5-N-methyl- 165-167mehylamino- (2-chlorobenzylacetone. aminomethyl) 0 N-3,4-diehlorobenzyl-5-met-hyl-5-N-methyl- 178-179 N-methylamino- (3,4-dichloroacetone.benzylaminomethyl). 10 N-4-methoxybenzy1- 5-methy1- N-methyl- 186-188N-methylamino- (qnethoxybenzylacetone. aminomethyl) 11N-3-methoxy-benzyl- 5-methyl-5-N-methyl- 159-162 N-methylamino-(3-methoxybenzylacetone. amtnomethyl) 12 N-benzyl-N-iso-5-methyl-5-N-iso- 190-198 propylaminopropylbenzylacetone. aminomethyl.13 N-3,4-dimeth0xy- 5-methyl-5-N-methyl 160-162 benzyl-N-methyl-(3,4-dimethoxyaminoacetone. henzylaminomethyl).

I claim: 1. A compound of the formula wherein R represents a monovalentbasic radical selected from the group which consists ofN-methyl-(Z-chlorobenzylamino), N-methyl-(3,4-dichlorobenzylamino), N-methyl-(4-methoxybenzylamino), N-methyl-(3-methoxybenzylamino), and Nmethyl (3,4 dimethoxybenzylamino).

2. 5 methyl 5 N methyl-(2-chlorobenzylaminomethyDhydantoin.

3. S-methyl 5 N methyl-(3,4-dichlorobenzylaminomethyl) hydantoin.

4. S-methyl 5 N methyl-(4-methoxybenzylaminomethyl)hydantoin.

5. S-methyl 5 N methyl-(3-methoxybenzylaminomethyl)hydantoin.

6. 5 methyl 5 N methyl-(3,4-dimethoxybenzylaminoethyl)hydantoin.

References Cited UNITED STATES PATENTS 2,290,281 7/ 1942 Henze 260309.52,615,897 10/1952 Persch et al 260309.5

OTHER REFERENCES Henze et al.: Jour. Amer. Chem. Soc. vol. 62, pp. 912-13 (1940 HENRY R. JILES, Primary Examiner. NATALIE TROUSOF, AssistantExaminer.

US. Cl. X.R.

